TY - JOUR
T1 - Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy
AU - Zhou, Yu Dong
AU - Lee, Sanghoon
AU - Jin, Zhe
AU - Wright, Moriah
AU - Smith, Stephen E.P.
AU - Anderson, Matthew P.
N1 - Funding Information:
We would like to thank C.B. Saper, J.S. Flier, D.K. Simon, G.D. Rosen, M.R. Kasten and M.W. Anderson for comments and suggestions, and G.D. Rosen for help on the Neurolucida system. This work was supported in part by the US National Institute of Neurological Disorders and Stroke R01 NS057444 (M.P.A.), US National Institute of Neurological Disorders and Stroke K02 NS054674-03 (M.P.A.), the Nancy Lurie Marks Family Foundation (M.P.A.), Autism Speaks/US National Alliance for Autism Research (M.P.A.) and Beth Israel Deaconess Medical Center.
PY - 2009
Y1 - 2009
N2 - A subset of central glutamatergic synapses are coordinately pruned and matured by unresolved mechanisms during postnatal development. We report that the human epilepsy gene LGI1, encoding leucine-rich, glioma-inactivated protein-1 and mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We created transgenic mice either expressing a truncated mutant LGI1 (835delC) found in ADLTE or overexpressing a wild-type LGI1. We discovered that the normal postnatal maturation of presynaptic and postsynaptic functions was arrested by the 835delC mutant LGI1, and contrastingly, was magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission. Inhibitory transmission, by contrast, was unaffected. Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial γ-aminobutyric acid A (GABA A) receptor blockade. Thus, LGI1 represents a human gene mutated to promote epilepsy through impaired postnatal development of glutamatergic circuits (pages 1126-1127).
AB - A subset of central glutamatergic synapses are coordinately pruned and matured by unresolved mechanisms during postnatal development. We report that the human epilepsy gene LGI1, encoding leucine-rich, glioma-inactivated protein-1 and mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We created transgenic mice either expressing a truncated mutant LGI1 (835delC) found in ADLTE or overexpressing a wild-type LGI1. We discovered that the normal postnatal maturation of presynaptic and postsynaptic functions was arrested by the 835delC mutant LGI1, and contrastingly, was magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission. Inhibitory transmission, by contrast, was unaffected. Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial γ-aminobutyric acid A (GABA A) receptor blockade. Thus, LGI1 represents a human gene mutated to promote epilepsy through impaired postnatal development of glutamatergic circuits (pages 1126-1127).
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U2 - 10.1038/nm.2019
DO - 10.1038/nm.2019
M3 - Article
C2 - 19701204
AN - SCOPUS:70350494929
SN - 1078-8956
VL - 15
SP - 1208
EP - 1214
JO - Nature medicine
JF - Nature medicine
IS - 10
ER -